INTERVENTIONAL VASCULAR DIAGNOSTICS AND THERAPY. SeQuent Please NEO CLINICAL EVIDENCE AND COST / BENEFIT EFFECTIVENESS

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1 INTERVENTIONAL VASCULAR DIAGNOSTICS AND THERAPY SeQuent Please NEO CLINICAL EVIDENCE AND COST / BENEFIT EFFECTIVENESS

2 Table of Contents Overview SeQuent Please - DCB Scientific Publications SeQuent Please Study Overview SeQuent Please: ISR Lesions Study Overview SeQuent Please: de-novo Lesions Clinical Studies ISR Lesions Clinical Studies de-novo Lesions Limitations of DAPT Cost/Benefit Effectiveness Analyses Recommendations of the Guidelines of National and International Professional Societies 1. Excerpt from the ESC Recommendations 2. Excerpt from the DGK Recommendations 3. Excerpt from the NICE Recommendations Recommendation of the German DCB Consensus Group Executive Summary

3 SeQuent Please DCB with convincing Clinical Evidence Description Restenosis prevention remains a challenge in interventional cardiology. Treatment with the DCB-only offers a targeted, polymer-free and homogenous drug delivery designed to overcome the limitations of today s treatment options and will help to reduce the number of unnecessary stent implantations. The use of SeQuent Please (DCB only concept) is associated with unsurpassed efficacy in patients with ISR and de-novo lesions including SVD. The studies conducted with DCB based on the PACCOCATH coating technology (SeQuent Please) strongly support this alternative treatment form. Advantages of SeQuent Please are: - Shortened DAPT of 4 weeks for DCB-only - Polymer-free, homogenous and targeted drug delivery into the vessel wall - High bioavailability of paclitaxel and uniform drug distribution at the target lesion site with the coating matrix (PACCOCATH ) - Clinical evidence of efficacy (>22 published studies) - Recommendations of various medical societies and the ESC SeQuent Please NEO Next Generation DCB Description The success story of SeQuent Please continues with the next generation called SeQuent Please NEO. The new DCB SeQuent Please NEO combines the advanced crossing performance of B. Braun s rapid exchange PTCA balloon catheter SeQuent NEO with the well-proven paclitaxel releasing concept of SeQuent Please. Advantages of SeQuent Please NEO are: Enhanced tracking and pushability - Innovative hydrophilic shaft coating - Outstanding low tip and balloon profile Proven drug coating technology - Matrix coating with Iopromid and Paclitaxel Improved product portfolio - 49 sizes available - Long balloons available in 35 mm & 40 mm balloon length

4 Scientific Publications SeQuent Please NEO SCIENTIFIC PUBLICATIONS SEQUENT PLEASE 1. Study Overview SeQuent Please - Clinical Studies ISR-Lesions - Clinical Studies de-novo Lesions - Limitations of DAPT 2. Cost/Benefit Effectiveness Analyses

5 Study Overview SeQuent Please Overview Clinical Studies In-stent restenosis PACCOCATH ISR I / II Long-term results PEPCAD II Long-term results Kurashiki - Habara I Kurashiki - Habara II ISAR DESIRE III SEDUCE PEPCAD DES PEPCAD CHINA Allmalla et al Study De-novo Lesions / Small Vessels / Bifurcations PEPCAD I Long-term results PEPCAD IV PEPCAD V DEBAMI PERfECT PEPCAD CTO International SeQuent Please Registry OCTOPUS I INDICOR SeQuent Please Small Vessel Registry BABILON DCB Bifurcation Study (Spain) OCTOPUS II Late Lumen Enlargement Limitations of DAPT Patients with Risk of Thrombosis Patients with a High Risk of Bleeding Complications Cost/Effectiveness Analyses Cost/Effectiveness Analyses SeQuent Please Overview Recommendations of Medical Societies

6 SeQuent Please Clinical Studies on ISR Lesions Study Study aim Patients Status Follow Up Publication PACCOCATH ISR I / II SQP vs. POBA BMS-ISR 108 completed 6, 24, 72 month Scheller B et al. NEJM 2006; 355: Scheller B et al. Clin Res Cardiol 2008; 97: PEPCAD II SQP vs. DES BMS-ISR 131 completed 6, 12, 36 month Unverdorben M et al. Circulation 2009; 119: Kurashiki- Habara I SQP vs. POBA DES-ISR (Sirolimus) 50 completed 12 month Habara S et al. JACC Cardiovasc. Interv 2011; 4: Kurashiki- Habara II ISAR DESIRE III SQP vs. POBA BMS-ISR/DES-ISR SQP vs. POBA vs. Taxus Liberté DES-ISR 208 completed 12 month Habara S et al. Am Hear J 2013; 166(3): completed 8 month Byrne RA et al. Lancet 2013; 381: SEDUCE SQP vs. Xience V DES-ISR 50 completed 9 month Adriaenssens T et al. TCT 2012, session II, Coronary DCB Program Update PEPCAD DES SQP vs. POBA DES-ISR 110 completed 6, 12 month Rittger H et al. JACC 2012; 59: PEPCAD-CHINA SQP vs. Taxus Liberté DES-ISR 220 completed 9 month Xu B et al. JACC Cardiovasc Interv. 2014; 7(2): Almalla et al study SQP vs. Xience V DES-ISR 86 completed 12 month Almalla M et al. Cath Cardiovasc Interv 2013; doi: /ccd.25072

7 SeQuent Please Clinical Studies on de-novo Lesions Study Study aim Patients Status Follow Up Publication PEPCAD I SQP de-novo - Small Vessel 118 completed 6, 12, 36 month Unverdorben M et al. Cath Cardiovasc Interv. 2010; 99: PEPCAD IV PEPCAD V DEBAMI SQP + BMS vs. DES de- novo (Diabetics) SQP + BMS Bifurcations SQP + BMS AMI-STEMI 84 completed 9 month Rosli MA et al. EuroIntervention. 2011; 7 Suppl K:K completed 9 month Mathey D et al. EuroIntervention 2011; Suppl K: K completed 9, 12 month Koh TH et al. EuroPCR 2011 PERfECT SQP + EPC vs. EPC de-novo 120 completed 6, 12, 36 month Woehrle J et al. Heart 2011; 16: PEPCAD CTO SQP + BMS vs. DES CTO 48 completed 6 month Woehrle J, Werner GS CCI 2013; 81(5):793-9 SQP-Registry SQP all comer 2095 completed 9 month Woehrle J et al. JACC 2012; 60: OCTOPUS INDICOR SVD Registry BMS+SQP vs. Xience V SQP + BMS vs. CFB + SQP SQP De novo - Small Vessel 95 completed 6 month Poerner TC et al. ACC 2012; Summit 97 completed 9 month Kaul U et al. Indian Heart J 2013; 65: completed 9 month Zeymer U et al. Heart 2014; 100(4):311-6 DCB Bifurcation Study (Spain) SQP SB Dilation 100 completed 12 month Juan A et al. J Interven Cardiol 2013; 26: OCTOPUS II OCT DCB without stenting 48 completed 6 month Poerner T et al. Presentation 2013, Klinik für Innere Medizin, Universitätsklinikum Jena, Germany Kleber et al. DCB for de-novo lesions 56 completed 4 month Kleber F et al. Clin Res Cardiol 2014 Ongoing Studies: DEB only All Comer Registry, PEPCAD BIF, BASKET SMALL 2

8 Explanations: BIF BMS BMS-ISR BVS CABG CFB CFX CTO DAPT DCB DES DES-ISR DGK DRG EES ESC EPC FFR IQWiG ISR ISR I ISR II LAD LLL MACE MI MTAC NHS NICE NLG NSTEMI OAC Bifurcation Bare Metal Stent Bare Metal Stent In-Stent Restenosis Bioresorbable Vascular Scaffold Coronary Artery Bypass Graft[ing] Coroflex Blue Coroflex Chronic Total Occlusion Dual Antiplatelet Therapy Drug-Coated Balloon Drug-Eluting Stent Drug Eluting Stent In-Stent Restenosis Deutsche Gesellschaft für Kardiologie-, Herz- und Kreislaufforschung Diagnosis-Related Groups Everolimus-Eluting Stent European Society of Cardiology Endothelial Progenitor Cell Fractional Flow Reserve Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen In-Stent Restenosis Paccocath In-Stent Restenosis Trial I Paccocath In-Stent Restenosis Trial II Left Anterior Descending Late Lumen Loss Major Advers Cardiac Events Myocardial Infarction Medical Technologies Advisory Committee National Health Service National Institute for Health and Clinical Excellence Net Lumen Gain Non-ST-Segment Elevation Myocardial Infarction Oral Anticoagulation OCT Optical Coherence Tomography PACCOCATH SeQuent Please Paclitaxel Coating Technology PCI Percutaneous Coronary Intervention PEPCAD I Paclitaxel-Eluting PTCA-Balloon Catheter to Treat Small Vessel Coronary Artery Disease PEPCAD II Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease to Treat In-Stent Restenosis: A Comparison to the Paclitaxel-Eluting TAXUS Stent PES Paclitaxel-Eluting Stent POBA Plain Old Balloon Angioplasty PTCA Percutaneous Transluminal Coronary Angioplasty QCA Quantitative Coronary Angiography RCA Right Coronary Artery RCX Ramus Circumflexus SB Sidebranch SD Standard Deviation SES Sirolimus-Eluting Stent SQP STEMI SVD TIMI TLR TLF single-blind double-blind single-arm all comers SeQuent Please ST-Elevation Myocardial Infarction Small Vessel Disease Thrombolysis in Myocardial Infarction Target Lesion Revascularization Target Lesion Failure Investigator is aware of group allocation Group allocation is unknown during treatment and evaluation no control group no significant, exclusion criteria

9 CLINICAL STUDIES In-Stent Restenosis In-Stent Restenosis

10 PACCOCATH ISR I / II DCB Pilot Studies for ISR in BMS Treatment of Coronary In-Stent Restenosis with a Paclitaxel-Coated Balloon Catheter Scheller B et al. NEJM 2006; 355: Scheller B et al. Clin Res Cardiol 2008; 97: Scheller B et al. JACC Cardiovasc. Interv 2012; 5: Description The treatment of coronary ISR is limited due to the common incidence of recurrent ISR in BMS-ISR. These studies assessed the efficacy and safety of DCB in patients with BMS-ISR. Overall 108 patients (ISR I: 52 & ISR II: 56) with an ISR were enrolled in these two prospective, randomized studies. Both multicenter double-blind studies compared the efficacy of a DCB (3 µg/mm2 balloon surface) with an uncoated balloon. The in-segment LLL was the primary endpoint of the study. Secondary endpoints were restenosis rate and MACE. Results In both evenly divided patient groups multivessel disease was present in more than 75% of the cases and the quantitative coronary angiography showed no significant differences in the baseline characteristics. Considerable differences were observed in terms of LLL, binary restenosis rate (see table) and clinically driven TLR. Furthermore rates for TLR, MACE and MI were also lower in the DCB group as compared to the POBA group. 12 (QCA: 6)-Month Follow-Up: Ø In-segment LLL (6 Month) Binary restenosisrate in-segment (6 Month) MI (12 Month) DCB POBA 0.11 ± 0.44 mm 0.8 ± 0.79 mm 3/54 (6 %) 25/54 (51 %) 1/54 (2 %) 5/54 (9 %) Conclusion TLR 2/54 (4 %) 20/54 (37 %) (12 Month) Treatment of coronary BMS-ISR with DCB significantly reduces the restenosis rate. These data show that the inhibition of restenosis by local drug delivery does not re- MACE 9 % 44 % (12 Month) quire a stent implantation and sustained drug release in the treated vessel wall. In fact, the drug delivery based on Paccocath technology appears to be homogenous and well dosed and thereby reducing neointimal hyperplasia which is caused by the mechanical action of the inflated balloon.

11 PACCOCATH ISR I / II DCB Pilot Studies for ISR in BMS Long-term results (24 and 60 months) Clinical follow-up after 24 and 60 months is showing a low TLR rate for the DCB in BMS-ISR while being superior to POBA. At the 5-year long-term follow-up there was a significant advantage for the DCB. The rate of major adverse cardiac events showed that the majority of events occurred within the first 12 months but over the whole time period the DCB is superior (see diagram mentioned below). 24-Month Follow-Up: 60-Month Follow-Up: DCB POBA DCB POBA MI 1/54 (2 %) 5/54 (9 %) MI 5/54 (9.3 %) 8/54 (14.8 %) TLR 3/54 (6 %) 20/54 (37 %) Stent thrombosis 0 0 MACE 11 % 46 % TLR 5/54 (9.3 %) 21/54 (38.9 %) MACE 27.8 % 59.3 % Kaplan-Meier Curve: Freedom from MACE

12 PEPCAD II (The Paclitaxel-Eluting PTCA Balloon in Coronary Artery Disease) SeQuent Please vs. Taxus Libertè for the Treatment of BMS-ISR Paclitaxel-Coated Balloon Catheter vs. Paclitaxel-Coated Stent for the Treatment of Coronary In-Stent Restenosis Unverdorben M et al. Circulation 2009; 119: Unverdorben M et al. EuroIntervention pii: doi: /EIJY14M08_12 Description The treatment of BMS-ISR with DCB in comparison to POBA is associated with a low LLL and less MACE. In this study the efficacy and safety of DCB was compared to PES. DCB and PES were compared in terms of safety and efficacy. 131 patients with an BMS-ISR were randomly assigned to two groups. They were either treated with a DCB or a PES. The main inclusion criteria were diameter stenosis of 70% and 22 mm in length with a vessel diameter of mm. The in-segment LLL was the primary endpoint of the study. Results Patients were randomized 1:1 (DCB: 66 patients; DES: 65 patients). The QCA revealed no significant differences in lesion-related risk factors. The restenosis rate after 6 months was 7% for the DCB compared to 20% for the PES. All documented results from PEPCAD II are comparable to those from the historic PACCOCATH ISR I / II trials and confirm the clinical efficacy of the DCB. 12-Month Follow-Up/6-Month angiogr. FU: Ø In-segment LLL (6 Month) Binary restenosisrate in-segment (6 Month) MI (12 Month) TLR (12 Month) Conclusion Treatment of coronary ISR in BMS with DCB showed a promising alternative while being at least as effective and well tolerated as PES. According to the as treated evaluation MACE (12 Month) 7.6% 16.9% the DCB was superior to the PES. Therefore, no further stent implantation is required for the treatment of BMS-ISR and inhibition of re-restenosis. Thus the DAPT can be shortened to a period of 4 12 weeks. In summary, the DCB was superior to the PES. DCB DES 0.17 ± 0.42 mm 0.38 ± 0.61 mm 4/66 (7%) 12/65 (20.3%) 0 1/65 (1.5%) 4/66 (6.3%) 10/65 (15.4%)

13 PEPCAD II SeQuent Please vs. Taxus Libertè for the Treatment of BMS-ISR Long-term results at 36 month While the TLR rate of DCB only slightly increased from 6.3% at 12 month to 7.6% at 36 month, the corresponding TLR rate in the DES group was 18.5% vs. 15.4% at 12 months. During the entire three years there was no thrombosis in neither group. The DCB delivered sustainable positive clinical results up to 3 years with a strong trend towards lower MACE at 3 years as compared to DES. 36-Month Follow-Up: DCB DES MI 1/66 (1.5 %) 1/65 (1.5 %) TLR 5/66 (7.6 %) 12/65 (18.5 %) Thrombosis 0 0 MACE 15.2 % 27.7 % Kaplan-Meier curve - freedom from MACE:

14 Kurashiki - Habara I SeQuent Please vs. POBA for ISR in SES Effectiveness of Paclitaxel-Eluting Balloon Catheter in Patients with Sirolimus-Eluting Stent Restenosis Habara S et al. JACC Cardiovasc. Interv 2011; 4: Description Resulting from the increasing treatment of complex stenoses with DES, DES-ISR is another indication for DCB. This study aims to assess the efficacy of DCB in ISR after SES implantation. Overall 50 patients with a first-time ISR were treated with DCB or POBA after DES implantation (DCB vs. POBA). The lesion inclusion criteria were <26 mm in length with a vessel diameter of mm. Primary endpoint was LLL and secondary endpoints were the binary restenosis rate and MACE rates. Results Between both groups there was no significant difference in the patient baseline characteristics. Angiographic follow-up was done in 94% of all patients and revealed a considerably lower LLL for the DCB. Above all, the MACE rate in the DCB group was significantly lower as compared to the POBA group (4.3% vs. 41.7%). It should be noticed that all MACE were associated with revascularizations. 6-Month Follow-Up: DCB POBA Ø In-segment LLL 0.18 ± 0.45 mm 0.72 ± 0.55 mm Binary restenosisrate in-segment 2/23 (8.7%) 15/24 (62.5%) TLR 1/23 (4.3%) 10/24 (41.7%) Conclusion MACE 4.3 % 41.7% The DCB showed substantially better clinical and angiographic results in comparison to the treatment with POBA for patients with ISR after SES implantation. Based on the study s results DCB may be the preferred strategy to treat DES-ISR without current treatment limitations of DES.

15 Kurashiki - Habara II SeQuent Please vs. POBA for BMS-ISR and DES-ISR A multicenter randomized comparison of paclitaxel-coated balloon catheter with conventional balloon angioplasty in patients with bare-metal stent restenosis and drug-eluting stent restenosis Habara S et al. Am Hear J 2013; 166(3): Description The aim of this study was to evaluate the safety and efficacy of the DCB (SeQuent Please, B. Braun Melsungen AG) in BMS-ISR as well as in DES-ISR compared to POBA. Overall 208 patients with 213 restenotic lesions (BMS-ISR: 123 lesions, DES-ISR: 90 lesions) were enrolled in this prospective, multicenter, randomized (2:1) study carried out in 13 Japanese centers. Primary endpoint was target vessel failure after 6 month. Clinical and angiographic follow-up were done at 6 months in 207 patients (99.5%) with 208 lesions (97.7%). Results Target vessel failure was observed in 6.6% of the DCB group and in 31.0% in the POBA group (P <.001). Recurrent restenoses were observed in 4.3% in the DCB group and in 31.9% in the POBA group (P <.001). LLL was lower for the DCB group as compared to the POBA group (0.11 ± 0.33 mm vs ± 0.50 mm, P <.001) Conclusion In this randomized clinical study, the DCB showed significantly better clinical and angiographic results in comparison to POBA in patients with BMS-ISR and DES-ISR. 6-Month Follow-Up: Angiogr. Target Vessel Failure DCB (n=136) POBA (n=71) p-value 6.6% (9) 31.0% (22) <.001 LLL 0.11 ± ± 0.50 <.001 Binary restenosis rate Clinical 4.3% (6) 31.9% (22) <.001 DCB (n=136) POBA (n=71) p-value TLR 2.9% (4) 31.0% (22) <.001 MACE 6.6% (9) 31.0% (22) <.001

16 ISAR DESIRE III SeQuent Please vs. POBA vs. Taxus Liberte for ISR in Limus-Eluting stents Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial Byrne RA et al. Lancet 2013; 381: Description The aim of this study was to identify the optimal strategy for the treatment of restenosis in patients after limus-eluting stent implantation. In these patients, the efficacy of DCB, PES, and POBA was evaluated. The inclusion criteria of this prospective, randomized, controlled, multicenter study carried out in three German centers were lesions with a restenosis rate of at least 50% after implantation of a limus-eluting stent. Overall 402 patients were randomized in three groups (1:1:1) and were either treated with DCB (137), or PES (131), or solely with POBA (134). The study was single-blind, i.e. with regard to the angiographic evaluation. Primary endpoint was the diameter stenosis (DS%) after 6-8 months. 338 (84%) patients had an angiographic follow-up. Results 137 (34%) patients were assigned to the DCB group, 131 (33%) to the PES and 134 (33%) to the POBA group. 392 (98%) patients received clinical follow-up. The results did not show any significant differences with regard to diameter stenosis when comparing the DCB group and the PES group (38.0% [SD 21.5] vs. 37.4% [21.8]; P non-inferiority = 0.007). However, the results of the DCB and PES groups were superior to the POBA group (54.1% [25.0]; P superiority < for both control groups). 9-Month Follow-Up: Conclusion DCB angioplasty should be the method of choice to avoid stent-in-stent interventions. Diameter stenosis (%) Recurrent binary restenosis TLR Death or MI DCB DES POBA 38.0% 37.4% 54.1% 39 (26.5%) 30 (22.1%) 6 (4.4%) 34 (24.0%) 17 (13.5%) 9 (6.9%) 72 (56.7%) 56 (43.5%) 9 (6.8%)

17 SEDUCE SeQuent Please vs. Xience V for BMS-ISR SEDUCE (Safety and Efficacy of a Drug eluting balloon in Coronary artery restenosis): an OCT study 2012 Adriaenssens T et al. EuroIntervention 2014; 10: Description DES are associated with safety concerns due to the higher risk of late stent thrombosis related to incomplete endothelialization. By means of OCT, an evaluation of neointimal proliferation and stent endothelialization is possible. The SEDUCE study is aimed at comparing the treatment of BMS-ISR with DCB angioplasty versus EES implantation using OCT. 50 patients with ISR were randomized into two treatment groups, for i.e. DCB (SeQuent Please, B. Braun Melsungen AG) or the EES (Xience V, Abbott Laboratories). Primary endpoint was the endothelial stent coverage, measured with OCT at 9 months. Results The DCB was superior to the EES, with 1.4% vs. 3.2% isolated stent struts. In the EES group, the LLL value was lower (0.07 vs mm). However, this did not lead to better clinical results. The TLR rate in the DCB group was 4.2% vs. 8% in the EES group. Furthermore, in the DCB group no stent thrombosis was observed, while one patient of the EES group had a stent thrombosis (0% vs. 4%). The results of the SEDUCE study showed that overall, the DCB is safe and effective Conclusion At the 9-month follow-up, there were less isolated stent struts in the DCB group compared to the EES group. Presumably this difference is due to the faster neointimal healing process after DCB angioplasty. The results of the recent study support the use of the DCB as a safe and effective treatment option for ISR. 9-Month Follow-Up: Total number of struts % of covered struts % of uncovered struts Late Loss (mm) in-stent DCB n = 20 EES n = 20 p-value < % 96.8% ,4% 3,2% Stent thrombosis 0 (0%) 1 (4%) TLR 1 (4.2%) 2 (8.0%) 0.576

18 PEPCAD DES SeQuent Please for DES-ISR A Prospective, Randomized Trial of a Paclitaxel-coated Balloon vs. uncoated Balloon Angioplasty in Patients with Drug-Eluting Stent Restenosis Rittger H et al. JACC 2012; 59: Description Caused by the continuous increase of DES implantation in challenging lesions, the number of DES-ISR is increasing. As several studies already have proven the superiority of the DCB for ISR in BMS over POBA and the non-inferiority in comparison to PES, this randomized, multicenter, single blind study is designed to determine the efficacy of DCB in DES-ISR. Main inclusion criterion was a DES-ISR in a native coronary artery with a diameter of mm and a lesion length of 22 mm. All current DES were included, whether coated with sirolimus, everolimus or paclitaxel. 110 patients were enrolled of whom 72 subjects were treated with a DCB and 38 subjects with POBA (randomized 2:1). More than half of the patients had at least two stent layers. Primary endpoint was LLL at 6 month. There were clinical follow-ups at 6 and 12 month in 100% of all included patients. Results Baseline characteristics did not differ between both groups, except the DCB group being slightly older. After 6 months, LLL in the target lesion was 0.43 mm for the DCB group and 1.03 mm for the POBA group Conclusion DCB treatment was superior in terms of angiographic and clinical outcomes as compared to POBA. LLL and binary restenosis rate were significantly lower. The MACE rate in the DCB group compared to the POBA group was significantly reduced. Consequently, the DCB is a superior alternative to treat DES-ISR compared to POBA. Over 50% of all patients had 2-5 stent layers. 6- and 12-Month Follow-Up: Ø In-segment LLL Binary restenosis rate in-segment 6 Month 12 Month DCB POBA DCB POBA 0.43 ± 0.61 mm 1.03 ± 0.77 mm 17.2 % 61.3% MI (target vessel) 0 (0%) 1 (2.6%) 0 (0%) 2 (5.2%) TLR MACE 11/72 (15.3 %) 12/72 (16.7 %) 14/38 (36.8 %) 19/38 (50.0 %) 11/72 (15.3 %) 12/72 (16.7 %) 14/38 (36.8 %) 20/38 (52.6 %)

19 PEPCAD China SeQuent Please vs. Taxus Liberté for DES-ISR A Prospective, Multicenter, Randomized Trial of Paclitaxel-Coated Balloon Versus Paclitaxel-Eluting Stent for the Treatment of Drug-Eluting Stent In-Stent Restenosis Xu B et al. JACC Cardiovasc Interv. 2014; 7(2): Description The treatment of DES-ISR remains to be a challenge. ISAR-DESIRE 3 showed that the DCB could be a good alternative treatment for patients with restenosis after implantation of a limus-eluting stent, however further clinical studies need to support this claim. Furthermore, there is still no published DCB study for the treatment of ISR in a Chinese patient population. The PEPCAD China ISR study evaluates the safety and efficacy of DCB in a non-european patient population with DES- ISR. 215 patients were enrolled in this single-blind, prospective, multicenter, randomized (1:1) study carried out in 17 Chinese centers. Patients with DES-ISR were treated either with a DCB (SeQuent Please, B. Braun Melsungen AG, Melsungen, Germany) or with a PES (Taxus Liberté, Boston Scientific, Natick, Massachusetts). The primary endpoint was in-segment LLL after 9 month. 9 month follow-up was available in 81.3% of all recruited patients while the 12 month clinical follow-up was concluded in all patients (100.0%). Results LLL was lower for the DCB group compared to the DES group (0.46 ± 0.51 mm vs ± 0.61 mm, P < 0.32). Recurrent restenoses were observed in 18.6% of all cases in the DCB group and 23.8% in the DES group (P < 0.39). The TLF rate was 16.5% in the DCB group compared to 16.0 % in the DES group (P < 0.92). Conclusion This multicenter, randomized study showed the safety and efficacy of DCB angioplasty as well as the non-inferiority compared to DES in the treatment of a non-european population with ISR after limus-eluting stent ISR. 9- and 12-Month Follow-Up: Angiographic DCB (n=93) DES (n=82) p-value LLL in-segment 0.46 ± 0, ± Binary restenosis rate Clinical 18.6% (18) 23.8% (20) 0.39 DCB (n=109) DES (n=106) p-value TLF 16.5% (18) 16.0% (17) 0.92 Stent thrombosis 0.9% (1) 0.9% (1) 1.00

20 Almalla et al study SeQuent Please vs. Xience V for DES-ISR Paclitaxel-Eluting Balloon vs. Everolimus-Eluting Stent for Treatment of Drug-Eluting Stent Restenosis Almalla M et al. Cath Cardiovasc Interv 2014; 83 (6):881-7 Description This non-randomized single-center study with a historical control arm compared the clinical 1-year results of DCB angioplasty (SeQuent Please, B. Braun Melsungen AG) to the second-generation EES (Xience V, Abbott Laboratories) to treat DES-ISR. 46 patients with DES-ISR were treated with SeQuent Please and 40 patients with Xience V. Primary endpoint was freedom from MACE after one year. Secondary endpoints were freedom from TLR and freedom from definite stent thrombosis. The clinical follow-up was conducted by an independent trial coordinator after 22±11 months (DCB) and 25±19 months (EES). Results MACE rates were significantly lower in the DCB group (DCB 8.6% vs. EES 27.5%). The TLR rate in the DCB group was 4.3% vs. 22.5% in the EES group. Furthermore, in the DCB group no stent thrombosis was observed, while one patient of the EES group had a stent thrombosis (0% vs. 2.5%). 12-Month Follow-Up: DCB n=46 EES n=40 p-value MACE 4 (8.6%) 11 (27.5%) TLR 2 (4.3%) 9 (22.5%) Conclusion After one year, treatment of patients with DES-ISR with SeQuent Please resulted in a significantly lower MACE and TLR rates as compared to Xience V. Stent thrombosis 0 (0%) 1 (2.5%) 0.465

21 CLINICAL STUDIES de-novo Lesions de-novo Lesions

22 PEPCAD I (The Paclitaxel-Eluting PTCA Balloon in Coronary Artery Disease) SeQuent Please for SVD Treatment of Small Coronary Arteries with a Paclitaxel-Coated Balloon Catheter Unverdorben M et al. Cath Cardiovasc Interv. 2010; 99: Unverdorben M et al. EuroIntervention. 2013; 9 (5):620-8 Description The treatment of SVD with PCI is limited by the high restenosis rate. Therefore, the study evaluated the use of DCB angioplasty in this indication. 118 patients with de novo lesions in small vessels were treated with a DCB (SeQuent Please, B. Braun Melsungen AG). Main inclusion criteria for enrolment were lesions with a diameter stenosis 70% and 22 mm in length and a vessel diameter of mm. The primary endpoint was in-segment LLL. Results Of the total number of patients with a mean vessel diameter of 2.35 ± 0.19 mm, 82 persons (70 %) were treated with DCB only, whereas 32 patients needed an additional BMS. The patient group with an added BMS revealed a significant correlation between the geographic mismatch (miss between area of coated balloon dilation and stent implantation) and the occurrence of a restenosis. After 6 month follow-up a total mean in-segment LLL of 0.28 ±0.53 mm was observed, while in the group treated with DCB only the in-segment LLL was 0.16 ±0.38 mm. Conclusion 12 (QCA: 6)-Month Follow-Up: Ø In-segment LLL (6 Month) Binary restenosis rate in-segment (6 Month) MI (12 Month) TLR (12 Month) MACE (12 Month) DCB DCB + BMS 0.16 ± 0.38 mm 0.62 ± 0.73 mm 4/82 (5.5 %) 13/32 (44.8 %) 1/82 (1.3 %) 1/32 (3.1 %) 4/82 (4.9 %) 9/32 (28.1 %) 6.1 % 37.5 % Treatment of lesions in small coronary arteries with a DCB had a low restenosis rate. Furthermore, the majority of restenoses in the overall group resulted from a geographic mismatch while using an additional BMS. Consequently, the single use of DCB (DCB-only) leads to outstanding angiographic and clinical results. When using the combination of DCB+BMS, results were not as favorable as in the DCB-only group because of the geographic mismatch.

23 PEPCAD I SeQuent Please for SVD Long-term results at 36-Month The TLR rate of the DCB only group remains low at 4.9 %. The TLR rate of the combination group with DCB + BMS increased from 28.1% in the first 6 months up to 34.4% at 3 years. Neither in DCB only nor in DCB + BMS patients a thrombotic event was observed. The use of DCB without BMS showed excellent long-term results. DCB-only is the method of choice. 36-Month Follow-Up: DCB DCB + BMS MI 2/82 (2.4 %) 2/32 (6.3 %) TLR 4/82 (4.9 %) 11/32 (34.4 %) Stent thrombosis 0 2/32 (6.3 %) MACE 7.3 % 40.6 % Kaplan-Meier curve - cumulative freedom from MACE:

24 PEPCAD IV (The Paclitaxel-Eluting PTCA Balloon in Coronary Artery Disease) SeQuent Please + Coroflex Blue vs. Taxus Liberté for Diabetics with de-novo Stenoses Paclitaxel-Eluting Balloon Angioplasty and Cobalt-Chromium Stents vs. Conventional Angioplasty and Paclitaxel-Eluting Stents in the Treatment of Native Coronary Artery Stenoses in Patients with Diabetes Mellitus Rosli MA et al. EuroIntervention. 2011; 7 Suppl K:K83-92 Description High recurrence rates after PCI in diabetics were reported in the literature. Based on the promising data of DCB, an investigation of its efficacy in this diabetic patient group was initiated. Overall 84 patients were randomly assigned to either treatment group, i.e. DCB followed by BMS treatment or DES implantation. Only patients with diabetes mellitus and de novo stenoses in diameters of 2.5 mm and 3.5 mm and lesion lengths of 10 mm and 22 mm were enrolled. Primary endpoint was LLL after 9 month. Results 45 patients were treated with DCB + BMS (SeQuent Please + Coroflex Blue, B. Braun Melsungen AG), while 39 patients received a DES (TAXUS Liberté, Boston Scientific). Patient- and lesion-related risk factors were statistically comparable with the exception of higher age. The lesion characteristics were not statistically different. Kaplan-Meier analysis of the event free survival during the 9-month clinical follow-up showed a strong similarity after 10.2 ± 3.8 month. LLL, TLR and MACE rates revealed no significant differences. 9-Month Follow-Up: DCB + BMS DES Ø In-segment LLL 0.37 ± 0.59 mm 0.35 ± 0.63 mm MI 1/45 (2.2 %) 1/39 (2.6 %) TLR 3/45 (8.9 %) 4/39 (10.3 %) Stent thrombosis 0 1/39 (2.6 %) MACE 13.3 % 15.4 % Conclusion The clinical and angiographic results were not statistically different in both groups. DCB with subsequent BMS implantation and DES implantation were similar in terms of safety and efficacy.

25 PEPCAD V (The Paclitaxel-Eluting PTCA Balloon in Coronary Artery Disease) SeQuent Please + Coroflex in Bifurcations Treatment of bifurcation lesions with a Drug-Eluting Balloon Mathey D et al. EuroIntervention 2011; Suppl K: K61-65 Description Interventions in bifurcation lesions are often very complex and do not deliver satisfying long-term results. The aim of this first study in bifurcations was to evaluate the safety and efficacy of DCB in this lesion subset. 28 patients with a bifurcation lesion were enrolled. The main branch as well as the side branch were dilated with a DCB (SeQuent Please, B. Braun Melsungen AG). A BMS was implanted in the main branch. Only when the side branch had a TIMI flow of less than 3 and/or a stenosis of 50% an additional BMS was implanted. Results A procedural success of 100% was reported, while angiographic success was 97% for the main branch in comparison to 89% for the side branch. During the follow-up two patients (1 definite & 1 probable) had late stent thrombosis. Altogether three patients had an angiographic restenosis, only one clinically driven TLR was needed. Main branch Side branch % Stenosis: 9-Month Follow-up pre PCI post PCI 9 months 9-Month Follow-Up: Ø In-segment LLL (maine branch) Ø In-segment LLL (side branch) DCB + BMS 0.38 ± 0.46 mm 0.21 ± 0.48 mm TLR 1/28 (3.6 %) Stent thrombosis 2/28 (7.1 %) MACE (30 days) 0 % The LLL for the side branch was 0.12 ±0.40 mm when using only the DCB which is very low as compared to the treatment with additional implantation of a BMS with 0.66 ±0.59 mm. Conclusion Treatment of bifurcation lesions with DCB offered promising results and can be considered as an innovative alternative. The experience regarding the use of DCB in combination with BMS must be further expanded. The results showed a low LLL in the side branch.

26 DEBAMI (Drug Coated Balloon in Acute Myocardial Infarction) SeQuent Please + Coroflex Blue for Acute Myocardial Infarction A single-arm Safety and Feasibility Trial of Primary Percutaneous Coronary Intervention in ST-Elevation using Paclitaxel-Eluting Balloon and Bare Metal Stents Koh TH et al. EuroPCR 2011 Description This is the first study to assess the safety and feasibility of treating acute MIs with a combination of DCB and BMS. 30 patients were enrolled to treat MI with ST-Elevation after less than 12 hours since the onset of symptoms. Furthermore, de novo lesions of >50% with a reference diameter of mm and up to the maximal available length of a single DCB/BMS were treated. As much thrombus material as possible was removed in all patients to allow an optimal contact of the DCB with the vessel wall. All lesions were predilated using a semi-compliant balloon followed by DCB dilatation (SeQuent Please, B. Braun Melsungen AG). Afterwards the stent was deployed with a DCB overlap of 2 mm on each side. Primary endpoint was the TLR rate at 12 month. Results Within the first 6 months, two late stent thromboses were reported leading to one revascularization. After 12 month clinical follow-up, three ISR occurred and only one required a revascularization. A major problem was the restenosis at stent edge. This was directly associated with geographic mismatch, when the area covered by the stent was not properly treated by the DCB. This kind of geographic mismatch led to a considerable risk of an increased restenosis rate. The in-stent LLL excluding stent thrombosis was 0.40 mm, the in-segment LLL was 0.42 mm respectively. The in-segment binary restenoses were 3x type I, 1x type II und 1x type IV. 12 (QCA: 9)-Month Follow-up Ø In-segment LLL (9 Month) Binary restenosis rate in-segment (9 Month) TLR (12 Month) DCB + BMS % 5/30 (16.7 %) Conclusion This first small study demonstrated the safety of treating STEMI patients with a combination of DCB and BMS. Efficacy needs to be further evaluated. To improve results it is necessary to modify stenting techniques to avoid geographic mismatch and to use novel DAPT. Stent thrombosis (12 Month) MACE (12 Month) 2/30 (6.67 %) 16.7 %

27 PERfECT-Stent Studie SeQuent Please + EPC-Stent vs. EPC-Stent for de-novo Stenoses Prospective randomized Trial evaluating a Paclitaxel-coated Balloon in Patients treated with Endothelial Progenitor Cell capturing Stents for de novo Coronary Artery Disease Woehrle J et al. Heart 2011; 16: Description PCI with stent implantation is restricted by the occurrence of restenosis and the risk of stent thrombosis. EPC-capturing stents which are covered with antibodies can lead to faster endothelialization of the stent struts and therefore reduce the need for DAPT. The aim of the study was to evaluate the combination of a DCB together with an EPC stent in de novo lesions to reduce the risk of neointimal proliferation. In this multicenter single-blind study 120 patients were randomly assigned, treated with either a DCB + EPC stent (62 subjects) or with an EPC stent alone (58 subjects). Primary endpoint was in-stent LLL. Results There were no differences in baseline parameters of both patient groups. Angiographic follow-up was available in 96% of all patients. The restenosis rate was dramatically lower with only 5.1% for the combination of DCB+EPC in contrast to 23.2% in the EPC stent group. The clinical endpoint (cardiac death, TLR & MI caused by target vessel) was significantly lower with only 4.8 % in the DCB+EPC group compared to 17.2 % in the EPC stent group. During the entire study, only 3 months of DAPT were administered. There was no stent thrombosis in the EPC + DCB group, while in the EPC stent group one stent thrombosis occurred (1/1.7%). 6-Month Follow-Up: DCB + EPC EPC- Stent p-value Ø In-stent LLL 0.34 ± 0.45 mm 0.88 ± 0.48 mm < Binary restenosis rate in-segment 5.1 % 23.2 % Stent thrombosis 0 1 (1.7 %) 0.48 TLR 3/62 (4.8 %) 9/58 (15.5 %) 0.07 MACE 4.8 % 17.2 % Conclusion According to this study the combination of EPC stents with DCB was superior to EPC stent only for de novo lesions. The additional dilation with DCB reduced the known higher EPC group LLL. Despite the reduced DAPT of only 3 months there were no stent thromboses detected in the group with EPC + DCB.

28 PEPCAD CTO (The Paclitaxel-Eluting PTCA Balloon in Coronary Artery Disease) Pilot study SeQuent Please + Coroflex Blue vs. DES for Chronic Total Occlusions Paclitaxel-Eluting Balloons after Bare Metal Stent Placement in Successfully Recanalized Chronic Total Coronary Occlusions Woehrle J, Werner GS CCI 2013; 81(5):793-9 Description When using DES, the risk of late stent thrombosis due to incomplete endothelialization still remains a critical point in patient care. Furthermore, the risk of restenosis is not limited to the stented area, but is also possible at the proximal and distal segments of the stent. By use of homogenous drug distribution of a DCB with PACCOCATH technology, neointimal proliferation is consistently reduced and therefore a more complete and faster endothelialization may be possible. The use of a longer DCB compared to the stented segment prevents stenosis at the stent edges. This matched dual center study compared the historic results of a DES study and the combination of BMS implantation followed by DCB dilation in successfully revascularized CTO. 48 patients were enrolled and matched with a DES cohort dilatation. Recanalization BMS implantation DCB dilatation Inclusion criteria were patients with a CTO (TIMI flow of 0) and an estimated minimum occlusion duration of at least 3 months in a native coronary artery (reference diameter mm) without any ISR Results In both groups the patient- and lesion-related baseline parameters were comparable. The main criteria for matching with a historic DES group were length of the stented segment, diabetes rate and the reference diameter. The LLL and the restenosis rate were comparable, and there were no significant differences with respect to MACE and TLR after 12 months. After treatment with a DES one late stent thrombosis occurred in comparison to none in the DCB + BMS group. Conclusion The study showed no significant differences for the angiographic and clinical results. An average of three DCBs was used for a complete drug delivery in the entire stented area. The DCB was an alternative for patients in need for shortened DAPT/anticoagulation. 12 (QCA: 6)-Month Follow-Up Ø CTO localization LLL (6 Month) Binary restenosis rate in-segment (6 Month) TLR (12 Month) MACE (12 Month) DCB + BMS DES 0.33 mm 0.26 mm 27.7 % 20.8 % 7/48 (14.6 %) 7/48 (14.6 %) 14.6 % 18.8 % Stent thrombosis 0 (0 %) 1 (2.1 %)

29 SeQuent Please International Registry World-wide all comer Registry for SeQuent Please SeQuent Please World Wide Registry: A Large-Scale Registry Study of a Paclitaxel-Coated Balloon Woehrle J et al. JACC 2012; 60: Description Several randomized studies already demonstrated the usefulness of DCB treatment. The SeQuent Please registry evaluates safety and efficacy of DCB with optional BMS implantation in real-world daily routine. Only patients with contraindications for DAPT were excluded. The all-comer registry enrolled 2,095 patients with 2,234 lesions. The DCB should be dilated in the lesion and extended 2-3 mm distally beyond the lesion lengths. In the event that a BMS is placed outside the dilated segment, another DCB should be inflated to fully cover the stented area with paclitaxel. Primary endpoint was clinically driven TLR rate at 9 month. Results BMS-ISR DES-ISR de-novo DCB-only de-novo DCB + BMS Patients (2.095) Lesions (2.234) The patients were predominantly male (74.1%) with common cardiovascular disease risk factors (85.7% hypertension, 74.5% hyperlipidemia, 36% diabetes, 41.6% with a history of smoking and 6.3% hemodialysis dependent patients). According to AHA/ACC one third of the lesions was classified as B/2 or C, while target lesions were located at: 41.3 % LAD, 24.6 RCX and 29.1% RCA and 5% others. Nearly half (48.7%) were diffusely diseased vessels with 13.1% ostial lesions DCB were used with a mean lesion length of 17.3 ±8.0 mm and a vessel diameter of 2.9 ±0.5 mm.

30 SeQuent Please International Registry World-wide all comer Registry for SeQuent Please SeQuent Please World Wide Registry: A Large-Scale Registry Study of a Paclitaxel-Coated Balloon Woehrle J et al. JACC 2012; 60: Results MACE is defined as a composite of cardiac death, MI and ischemia driven TLR. 9-Month Follow-Up: MI Cardiac Death TVR TLR MACE All comers 0.8 % 1.8 % 6.2 % 5.2 % 6.7 % The registry compared the results between patients with DES-ISR and BMS-ISR. 9-Month Follow-Up (ISR): Patients Lesions MI Cardiac death TVR TLR MACE DES-ISR % 0.7 % 10.1 % 9.6 % 11.6 % BMS-ISR % 1.1 % 5.2 % 3.8 % 5.3 % 9-Month Follow-Up (DES -ISR): DES-ISR Paclitaxel Patients Lesions MI Cardiac death TVR TLR MACE % 0.8 % 9.2 % 8.3 % 11.7 % DES-ISR Non-Paclitaxel % 0.9 % 11.3 % 10.8 % 12.6 %

31 SeQuent Please International Registry World-wide all comer Registry for SeQuent Please: De-novo lesions Diabetic Patients SeQuent Please World Wide Registry: A Large-Scale Registry Study of a Paclitaxel-Coated Balloon Woehrle J et al. JACC 2012; 60: Results The registry compared the use of DCB in de-novo lesions with or without additional stent. The treatment in patients with diabetes was also investigated in this subgroup. 9-Month Follow-Up (de-novo): Patients Lesions MI Cardiac Death TVR TLR MACE DCB-only % 1.0 % 1.0 % 1.0 % 2.6 % DCB + BMS % 1.2 % 3.6 % 2.4 % 2.4 % 9-Month Follow-Up (de-novo in patients with diabetes): Cardiac Patients MI Death TVR TLR MACE DCB-only % 2.0 % 2.0 % 2.0 % 5.9 % DCB + BMS % 4.0 % 8.0 % 8.0 % 8.0 % Conclusion The world wide registry for SeQuent Please is currently the largest DCB registry in all comer patients including DES- ISR and BMS-ISR, de-novo lesions and patients with acute coronary syndrome. Altogether the registry revealed a low TLR rate after treatment of de-novo lesions and confirmed the results of randomized trials in clinical use. The TLR rate was significantly higher for DES-ISR in comparison to BMS-ISR and there were no differences between the different types of DES-ISR. The higher TLR rate in DES-ISR in comparison to BMS-ISR reflects the incidence of more complex lesions which led to the initial DES implantation. In the subgroup of patients with de-novo stenoses, SeQuent Please was associated with favorable 9-month clinical results. Patients with diabetes were associated with higher MACE rates. There were no thrombotic events after the use of DCB only.

32 OCTOPUS I SeQuent Please + Coroflex Blue vs. XIENCE V A Prospective Randomized Study Using Optical Coherence Tomography to assess endothelial coverage and neointimal proliferation at 6 month after implantation of a coronary everolimus-eluting stent compared with a bare metal stent postdilated with a paclitaxel-eluting balloon Poerner TC et al. ACC 2012; Summit Description First generation DES were associated with safety concerns due to the higher risk of late stent thrombosis related to incomplete endothelialization. By means of OCT, an evaluation of neointimal proliferation and stent endothelialization is possible. The study compares the implantation of a BMS (Coroflex Blue, B. Braun Melsungen AG) postdilated with a DCB (Se- Quent Please, B. Braun Melsungen AG) with the implantation of an EES (XIENCE V, Abbott Vascular) using OCT to assess endothelial coverage and neointimal proliferation. In total 91 patients with 116 lesions were randomized 1:1 into two groups. Primary endpoint was the endothelial coverage of the stents, measured with OCT at 6 months. Results 52 lesions were treated with a DES and compared to 64 lesions in the BMS-DCB group. Only three patients needed restenosis-driven TLR. There were no significant differences with regard to the maximal focal proliferation area and stent endothelialization area. Conclusion The study had a loss to follow-up rate of 25%. The DCB and the DES are effective to prevent restenosis. Both treatments show good stent endothelialization but BMS+DCB had slightly lower numerical values relative to the endothelialized stent surface. Notwithstanding the trauma induced to the vessel by the BMS, the combination of DCB+BMS provided good results. 6-Month Follow-Up: BMS-DCB n = 20 EES n = 20 p value Lesion number Not endothelialized (%) Max. focal proliferation (mm 2 ) 4.1 ± ± 7.3 n.s n.s. TLR 1 2 n.s.

33 INDICOR SeQuent Please and Coroflex Blue in de-novo Lesions The Paclitaxel-Eluting PTCA-Balloon Catheter in Combination with a Cobalt-Chromium Stent to Treat Coronary Artery Disease in a Real World Scenario Kaul U et al. Indian Heart J 2013; 65: Description Due to the rapidly evolving and spreading acceptance of DCB in PCI procedures, this Indian pilot study assessed the safety, feasibility and efficacy of the combination of DCB and BMS. The multicenter randomized real world trial enrolled 97 patients with 114 lesions with the intention to investigate whether stent first or DCB first provides better results. With BMS first followed by DCB a geographic mismatch can be avoided, since the stent is fluoroscopically visible and allows precise DCB placement. DCB first followed by BMS theoretically can result in improved drug delivery since no stent struts are covering the lesion during drug delivery into the vessel wall. Vessel reference diameter was mm with a lesion length of 10 to 25 mm. Primary endpoint was LLL at 6 months. Result The patient-related cardiovascular risk factors were not significantly different. DAPT was scheduled for three months in both groups. After follow-up the minimal lesion diameter in-segment was 2.07 ±0.93 mm for DCB first against similar 2.03 ±0.64 mm for BMS first. The study demonstrated no statistically significant difference between both procedures (e.g. MACE with a p value of 0.44). 12 (QCA: 6-Month Follow-Up) Ø in-stent LLL (6 Month) DCB + BMS BMS + DCB 0.50 ± 0.54 mm 0.49 ± 0.54 mm Stent thrombosis 3/49 (6.1 %) 1/48 (2.1 %) TLR (without thrombosis) 2/49 (4.1 %) 1/48 (2.1 %) (Lesion related) 10.2 % 4.2 % Conclusion The combination of DCB and BMS has the same results for LLL and MACE as polymer-based PES. The sequence of stenting and usage of DCB did not show any statistical differences for in-segment or in-stent LLL or MACE. If angioplasty with DCB results in the necessity of stenting ( bail-out ), the results for LLL are comparable to those with polymer-based PES.

34 SeQuent Please-Small Vessel Disease (SVD) Registry International SVD Register for SeQuent Please Safety and Efficacy of SeQuent Please Paclitaxel-coated balloon (Drug Coated Balloon, DCB) angioplasty for small vessel coronary artery disease in Europe and Asia with the intention to treat lesions without additional stenting Zeymer U et al. Heart 2014; 100(4):311-6 Description This multicenter, prospective, international Sequent Please SVD-registry evaluates the safety and efficacy of the DCBonly approach or the combined treatment with an additional BMS in de-novo lesions of small reference diameters ( 2.00 mm, 2.75 mm) for real-world daily routines. A total of 447 patients (66.1 ± 10.9 years of age, 36.7% diabetics) with 471 lesions were enrolled, 105 (23.5%) with an acute coronary syndrome, there of 41 (9.2%) STEMI- and 64 (14.8%) NSTEMI-patients. According to the DCB-only strategy for small vessels ( mm vessel diameter) the stenosis should be predilated with POBA. The coverage of every target lesion should be extended proximally and distally by the DCB by at least 2-3mm, the recommended balloon-to-vessel ratio being Furthermore, the DCB should be inflated at nominal pressure for at least 30 seconds. In case of a significant dissection and/or a restenosis of 30% after predilatation, a DCB plus BMS ( spot stenting ) or DES was recommended. Primary endpoint was clinically driven TLR rate at 9 months. Results after 9 Months MACE was defined as a composite of cardiac death, MI and ischemia driven TLR. Overall 384 (85.9%) patients received follow-up after 9 months. The initial procedural success rate was 99%. 27 (6%) patients needed additional BMS implantation. Follow-up after 9.4 ± 1.7 months revealed a TLR rate of 3.6% in the absence of target lesion thrombosis. Cardiac death or CABG were not observed. All Patients DCB-only DCB/BMS p value Patients Lesions TLR 14 (3.6%) 13 (3.6%) 1(4.0%) MACE 18 (4.7%) 17 (4.7%) 1 (4.0%) Conclusion In this large prospective clinical study in small vessel de-novo lesions, TLR and MACE rates were very low. The applied DCB-only strategy seems to be an attractive alternative to DES in the treatment of small vessels. Thrombosis rate in the target lesion 0 (0.0%) 0 (0.0%) 0 (0.0%) -

35 DCB Bifurcation Study (Spain) SeQuent Please vs. POBA for the Side Branch after provisional T Stenting in the Treatment of Bifurcation Stenosis Drug Eluting vs. Conventional Balloon for Side Branch Dilation in Coronary Bifurcations Treated by Provisional T Stenting Juan A et al. J Interven Cardiol 2013; 26: Description In bifurcation lesions, restenosis occurs predominantly at the ostium of the side branch. The endpoint of this study was LLL in the sidebranch treated with a DCB and POBA in bifurcations after provisional T-stenting. 50 patients were allocated to each group. In the DCB group, the ostium of the sidebranch was dilated with SeQuent Please, B. Braun Melsungen AG balloon. In both groups, a Taxus Liberté, Boston Scientific was implanted in the main vessel and postdilated with the kissing balloon technique. In case of a suboptimal result in the side branch, a Taxus Liberté stent was implanted in the POBA group and a BMS in the DCB group. Angiographic follow-up and IVUS were scheduled and done at 12 month. Results MACE rates (DCB 12 % vs. POBA 24%; p=0.11), as well as TLR rates (12% vs. 22%; p=0.16) were lower for the DCB group compared to the POBA group. Furthermore, the angiographic follow-up revealed lower restenosis rate for the DCB group (7% vs. 20%, p=0.08) with less late loss (0.09 vs. 0.40mm, p=0.01) in the sidebranch. Conclusion Compared to a POBA, the side branch DCB dilatation had a better angiographic outcome, less late loss and a lower restenosis rate at 12 months. 12-Month Follow-Up: DCB n = 50 POBA n = 50 p-value MACE 6 (12 %) 12 (24 %) 0.11 TLR 6 (12 %) 12 (24 %) 0.16 Sidebranch restenosis 3 (7 %) 9 (20 %) 0.08 Late Loss 0.09± ±

36 OCTOPUS II OCT to evaluate the Use of DCB without Stenting Evaluation of FFR-guided use of paclitaxel-eluting balloons (Sequent Please, B Braun) without stenting for elective PCI of de novo lesions: a prospective study with 6-month OCT follow-up Poerner T et al. Presentation 2013 Klinik für Innere Medizin I Universitätsklinikum Jena Germany Description The OCTOPUS II deals with elective PCI of de novo lesions with DCB without stenting. Therefore the study assessed feasibility of FFR-guided DCB-only treatment of stable CAD (all comers). The efficacy at 6 months and the safety of 4-week DAPT were evaluated. Moreover this study had the aim to investigate vessel remodeling and atherosclerosis progression using OCT at 6-month follow-up. The results should be used for comparison with equivalent data of lesion treatment with DES and BMS+DCB from the OCTOPUS I trial. Overall 48 patients (56 lesions) were enrolled in this single center study. LLL was the primary endpoint of the study. Secondary endpoints were TLR, NLG and vessel remodeling. Results There was no aneurysm formation. In the majority of cases the dissections completely healed at OCT followup. In addition there was no subacute vessel closure, probably due to DAPT. A significant restenosis did not occur. The MLD results of lesion treatment with DCB only were compared to equivalent data of lesion treatment with DES (Xience) and BMS+DCB (OCTOPUS I). Considerable differences were observed in terms of LLL at 6-month follow-up (see table). MLD was significantly greater after the index procedure compared to baseline, but also showed progressive increase at 6-month follow-up (p < 0.05; see figure) comparable to the MLD with DES. 6-Month Follow-Up (QCA): DES (Xience) BMS + DCB DCB-only LLL 0.29 ± ± ± 0.50 Conclusion The concept of an interventional DCB-only strategy of de-novo lesions in stable CAD is feasible and requires DAPT for only 4 weeks. The antiproliferative effects of paclitaxel induce persistent vessel remodeling leading to distinct late luminal gain at 6-month follow-up after a DCB angioplasty without stent implantation.